The behavior and physiology of animals and humans are regulated by endogenously generated 24-hour (circadian) rhythms. The suprachiasmatic nucleus (SCN) of the hypothalamus contains a circadian pacemaker that is essential for the regulation of circadian rhythms. Disruptions of circadian rhythms affect the health and well-being of millions of people and result from external disturbances such as shift-work and jet-lag and from constitutional variation of known (e.g. blindness) and unknown causes. A possible source of variation is the environment during development. The proposed project will study the development of circadian rhythms and the development of the SCN in an established animal model for circadian rhythms research, the hamster. The long-term goals of the project are: l. To understand the relationship between SCN organization and the regulation of circadian rhythms by examining this relationship during development, 2. To understand the mechanisms by which maternal physiology influences the fetal circadian pacemaker, and 3. To identify aspects of SCN development that might be subject to modification and therefore lead to long-term disruption of circadian regulation. The Specific Aims are to test hypotheses in four critical areas: l. The role of the pineal gland hormone melatonin in the development of the mammalian circadian pacemaker, 2. The role of a specific fetal neurotransmitter system (dopamine) in the development of the circadian pacemaker; 3. The prenatal development of the SCN at the time pacemaker function begins, and 4. The postnatal development of the SCN at the time neural connections from the eyes are formed. The functional development of the pacemaker will be assessed by measuring behavioral rhythms of young hamsters and of hamsters that have received grafts of the fetal SCN. The development of the SCN will be examined with anatomical methods that include immunohistochemistry, in situ hybridization, and receptor binding assays. A unique strain of hamsters with a mutation that affects circadian rhythms will also be used. Knowledge of SCN development is essential to understand the normal as well as abnormal regulation of circadian rhythms. In addition, maternal influence on the development of fetal circadian rhythms via a dopaminergic system indicates that drugs of abuse (e.g., cocaine) can affect the development of circadian rhythms.